This project investigates the mechanisms of initial resistance to infection and generation of protective immunity to bacteria. The immune response to Francisella tularensis strain LVS, a gram negative facultative intracellular bacterium, is being characterized in terms of the cell types involved and their products (cytokines and antibodies). Results to date have demonstrated that, similar to human infection. LVS is lethal for experimental animals (inbred mice) when administered either intraperitoneally (ip) or intravenously (iv), but the LD50 is four logs higher when administered subcutaneously (sc) or intradermally (id). Further, mice which survive sublethal sc or id infection are solidly immune to subsequent lethal ip or iv infection. Initial resistance to id infection is dependent on production of tumor necrosis factor and interferon gamma by macrophages and natural killer cells, respectively, since scid mice that lack mature T or B lymphocytes are able to survive sc or id infection for about 20 days. Studies in athymic nu/nu mice further demonstrate that mature T cells appears to be a major protective mechanism involved in generation of secondary immunity. However, a minor role for protective mechanism involved in generation of secondary immunity. However, a minor role for protection by antibacterial antibodies, that is itself dependent on T cells for expression, has been observed. Interestingly, substantial specific protective immunity to LVS develops in both normal and nu/nu mice, but not scid mice, within 2-3 days after id priming with LVS. These results implicate a cell type present in nu/nu mice but not in scid mice that is able to generate immunity rapidly. The mechanism(s) of this rapid generation of immunity may have important implications for development of vaccines to be used during community outbreaks of bacterial diseases.